Publications by authors named "Frank B Hu"

1,198 Publications

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Sugar-Sweetened Beverages, Artificially Sweetened Beverages, and Breast Cancer Risk: Results From 2 Prospective US Cohorts.

J Nutr 2021 Jun 10. Epub 2021 Jun 10.

Channing Division of Network Medicine, Department of Medicine, Brigham & Women's Hospital, and Harvard Medical School, Boston, MA, USA.

Background: Whether consumption of sugar-sweetened beverages (SSBs) or artificially sweetened beverages (ASBs) is associated with the risk of breast cancer is of public health interest.

Objectives: We sought to evaluate associations between consumption of SSBs and ASBs and risks of total and subtype-specific breast cancer.

Methods: We followed 82,713 women from the Nurses' Health Study (1980 to 2016) and 93,085 women from the Nurses' Health Study II (1991 to 2017). Cumulatively averaged intakes of SSBs and ASBs from FFQs were tested for associations with incident breast cancer cases and subtypes using Cox regression models. We also evaluated the associations stratified by menopausal status, physical activity, BMI, and alcohol intake.

Results: We documented 11,379 breast cancer cases during 4,655,153 person-years of follow-up. Consumption of SSBs or ASBs was not associated with total breast cancer risk: pooled HRs comparing extreme categories (≥1/day compared with <1/month) were 1.03 (95% CI, 0.95-1.12) and 0.96 (95% CI, 0.91-1.02), respectively. We observed a suggestive interaction by BMI using pooled data (P-interaction = 0.08), where a modestly higher risk of breast cancer with each serving per day increment of SSBs was found in lean women (HR, 1.06; 95% CI, 1.01-1.11) but not among overweight or obese women (HR, 1.00; 95% CI, 0.95-1.06). Moreover, in the pooled, fully adjusted analysis, compared to infrequent consumers (<1/month), those who consumed ≥1 serving of ASBs per day had a lower risk of luminal A breast tumors (HR, 0.90; 95% CI, 0.80-1.01; P-trend = 0.02).

Conclusions: Although no significant associations were observed overall, consumption of SSBs was associated with a slightly higher risk of breast cancer among lean women. This finding could have occurred by chance and needs confirmation. Our findings also suggest no substantial increase in the risk of breast cancer with consumption of ASBs.
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http://dx.doi.org/10.1093/jn/nxab172DOI Listing
June 2021

Plant-Based Diet Index and Metabolic Risk in Men: Exploring the Role of the Gut Microbiome.

J Nutr 2021 Jun 10. Epub 2021 Jun 10.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Healthy plant-based diet index (hPDI) is associated with a lower risk of cardiometabolic conditions, but its association as well as interactions with microbiome have not been elucidated.

Objectives: We aimed to investigate the interrelations between hPDI, gut microbiome, and cardiometabolic risk markers.

Methods: hPDI was derived from dietary assessments by a validated FFQ and was examined in relation to metagenomic profiles of 911 fecal samples collected from 303 men aged 71 ± 4 y with an average BMI (in kg/m2) of 25.2 ± 3.6 in the Men's Lifestyle Validation Study. Principal coordinate (PCo) analysis based on Bray-Curtis dissimilarity was conducted, and interactions between hPDI and PCo were examined by using a metabolic risk score composed of blood lipids, BMI, and glycated hemoglobin.

Results: After multivariable adjustment, hPDI was significantly associated with the relative abundance of 7 species and 9 pathways. In particular, higher hPDI was significantly associated with a higher relative abundance of Bacteroides cellulosilyticus and Eubacterium eligens, amino acid biosynthesis pathways (l-isoleucine biosynthesis I and III and l-valine biosynthesis), and the pathway of pyruvate fermentation to isobutanol. A favorable association between hPDI and the metabolic risk score was more pronounced among men with a higher PCo characterized by higher abundance of Bacteroides uniformis and lower abundance of Prevotella copri. At the individual species level, a similar interaction was also observed between hPDI and P. copri, as well as with Clostridium clostridioforme or Blautia hydrogenotrophica (all P-interaction < 0.01).

Conclusion: A greater adherence to a healthy plant-based diet by older men was associated with a microbial profile characterized by a higher abundance of multiple species, including B. cellulosilyticus and E. eligens, as well as pathways in amino acid metabolism and pyruvate fermentation. In addition, inverse associations between healthy plant-based diet and human metabolic risk may partially depend on microbial compositions.
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http://dx.doi.org/10.1093/jn/nxab175DOI Listing
June 2021

Glycolysis Metabolites and Risk of Atrial Fibrillation and Heart Failure in the PREDIMED Trial.

Metabolites 2021 May 11;11(5). Epub 2021 May 11.

Universitat Rovira i Virgili, Departament of Biochemistry and Biotechnology, Human Nutrition Unit, 43201 Reus, Spain.

The increased prevalence of atrial fibrillation (AF) and heart failure (HF) highlights the need to better understand the mechanisms underlying these cardiovascular diseases (CVDs). In the present study, we aimed to evaluate the association between glycolysis-related metabolites and the risk of AF and HF in a Mediterranean population at high risk of CVD. We used two case-control studies nested within the PREDIMED trial. A total of 512 incident AF cases matched to 734 controls, and 334 incident HF cases matched to 508 controls, were included. Plasma metabolites were quantified by using hydrophilic interaction liquid chromatography coupled with high-resolution negative ion mode MS detection. Conditional logistic regression analyses were performed. The results showed no association between baseline plasma glycolysis intermediates and other related metabolites with AF. Only phosphoglycerate was associated with a higher risk of HF (OR : 1.28; 95% CI: 1.06, 1.53). The present findings do not support a role of the glycolysis pathway in the pathogenesis of AF. However, the increased risk of HF associated with phosphoglycerate requires further studies.
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http://dx.doi.org/10.3390/metabo11050306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151758PMC
May 2021

Grading nutrition evidence: where to go from here?

Am J Clin Nutr 2021 Jun;113(6):1385-1387

Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA.

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http://dx.doi.org/10.1093/ajcn/nqab124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168365PMC
June 2021

Interplay between diet and gut microbiome, and circulating concentrations of trimethylamine N-oxide: findings from a longitudinal cohort of US men.

Gut 2021 Apr 29. Epub 2021 Apr 29.

Nutrition, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA

Objectives: Gut-produced trimethylamine N-oxide (TMAO) is postulated as a possible link between red meat intake and poor cardiometabolic health. We investigated whether gut microbiome could modify associations of dietary precursors with TMAO concentrations and cardiometabolic risk markers among free-living individuals.

Design: We collected up to two pairs of faecal samples (n=925) and two blood samples (n=473), 6 months apart, from 307 healthy men in the Men's Lifestyle Validation Study. Diet was assessed repeatedly using food-frequency questionnaires and diet records. We profiled faecal metagenome and metatranscriptome using shotgun sequencing and identified microbial taxonomic and functional features.

Results: TMAO concentrations were associated with the overall microbial compositions (permutational analysis of variance (PERMANOVA) test p=0.001). Multivariable taxa-wide association analysis identified 10 bacterial species whose abundance was significantly associated with plasma TMAO concentrations (false discovery rate <0.05). Higher habitual intake of red meat and choline was significantly associated with higher TMAO concentrations among participants who were microbial TMAO-producers (p<0.05), as characterised based on four abundant TMAO-predicting species, but not among other participants (for red meat=0.003; for choline, =0.03). Among abundant TMAO-predicting species, significantly strengthened the positive association between red meat intake and HbA1c levels (=0.01). Secondary analyses revealed that some functional features, including choline trimethylamine-lyase activating enzymes, were associated with TMAO concentrations.

Conclusion: We identified microbial taxa that were associated with TMAO concentrations and modified the associations of red meat intake with TMAO concentrations and cardiometabolic risk markers. Our data underscore the interplay between diet and gut microbiome in producing potentially bioactive metabolites that may modulate cardiometabolic health.
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http://dx.doi.org/10.1136/gutjnl-2020-322473DOI Listing
April 2021

The Structure of Relationships between the Human Exposome and Cardiometabolic Health: The Million Veteran Program.

Nutrients 2021 Apr 19;13(4). Epub 2021 Apr 19.

Massachusetts Veterans Epidemiology and Research Information Center (MAVERIC), Boston Veterans Affairs Healthcare System, Boston, MA 02130, USA.

The represents the array of dietary, lifestyle, and demographic factors to which an individual is exposed. Individual components of the exposome, or groups of components, are recognized as influencing many aspects of human physiology, including cardiometabolic health. However, the influence of the whole exposome on health outcomes is poorly understood and may differ substantially from the sum of its individual components. As such, studies of the complete exposome are more biologically representative than fragmented models based on subsets of factors. This study aimed to model the system of relationships underlying the way in which the diet, lifestyle, and demographic components of the overall exposome shapes the cardiometabolic risk profile. The current study included 36,496 US Veterans enrolled in the VA Million Veteran Program (MVP) who had complete assessments of their diet, lifestyle, demography, and markers of cardiometabolic health, including serum lipids, blood pressure, and glycemic control. The cohort was randomly divided into training and validation datasets. In the training dataset, we conducted two separate exploratory factor analyses (EFA) to identify common factors among exposures (diet, demographics, and physical activity) and laboratory measures (lipids, blood pressure, and glycemic control), respectively. In the validation dataset, we used multiple normal regression to examine the combined effects of exposure factors on the clinical factors representing cardiometabolic health. The mean ± SD age of participants was 62.4 ± 13.4 years for both the training and validation datasets. The EFA revealed 19 Exposure Common Factors and 5 Physiology Common Factors that explained the observed (measured) data. Multivariate regression in the validation dataset revealed the structure of associations between the Exposure Common Factors and the Physiology Common Factors. For example, we found that the factor for fruit consumption was inversely associated with the factor summarizing total cholesterol and low-density lipoprotein cholesterol (LDLC, = 0.008), and the latent construct describing light levels of physical activity was inversely associated with the blood pressure latent construct ( < 0.0001). We also found that a factor summarizing that participants who frequently consume whole milk are less likely to frequently consume skim milk, was positively associated with the latent constructs representing total cholesterol and LDLC as well as systolic and diastolic blood pressure ( = 0.0006 and <0.0001, respectively). Multiple multivariable-adjusted regression analyses of exposome factors allowed us to model the influence of the exposome as a whole. In this metadata-rich, prospective cohort of US Veterans, there was evidence of structural relationships between diet, lifestyle, and demographic exposures and subsequent markers of cardiometabolic health. This methodology could be applied to answer a variety of research questions about human health exposures that utilize electronic health record data and can accommodate continuous, ordinal, and binary data derived from questionnaires. Further work to explore the potential utility of including genetic risk scores and time-varying covariates is warranted.
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http://dx.doi.org/10.3390/nu13041364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073795PMC
April 2021

Body-Mass Index and Mortality among Adults with Incident Myocardial Infarction.

Am J Epidemiol 2021 Apr 27. Epub 2021 Apr 27.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.

The relation between body mass index (BMI, kg/m2) and mortality among survivors of myocardial infarction (MI) remains controversial. We examined the relationship of BMI before and after MI, and change in weight, with all-cause mortality among participants of the Nurses' Health Study (1980-2016) and Health Professionals Follow up Study (1988-2016) cohorts. During up to 36 years of follow-up, we documented 4856 incident nonfatal MI cases, among whom 2407 died. For the pre-MI and post-MI BMI, overweight was not associated with lower mortality. Obesity (BMI ≥ 30 kg/m2) was associated with higher risk of mortality. Compared to participants with post-MI BMI of 22.5-24.9, HRs were 1.16, 95% CI: 1.01, 1.34 for BMI 30-34.9 and 1.52, 95% CI: 1.27, 1.83 for BMI ≥ 35; Ptrend<0.001. Compared to stable weight from before to after MI, reduction of > 4 BMI units was associated with increased mortality, HR=1.53, 95%: CI 1.28, 1.83. This increase was only among participants who lost weight without improving physical activity or diet. Our findings showed no survival benefit of excess adiposity in relation to risk of mortality. Weight loss from before to after MI without lifestyle improvement may reflect reverse causation and disease severity.
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http://dx.doi.org/10.1093/aje/kwab126DOI Listing
April 2021

Building better guidelines for healthy and sustainable diets.

Am J Clin Nutr 2021 Apr 19. Epub 2021 Apr 19.

Departments of Nutrition and Epidemiology, Harvard TH Chan School of Public Health, Boston, MA, USA.

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http://dx.doi.org/10.1093/ajcn/nqab079DOI Listing
April 2021

HDL Containing Apolipoprotein C-III is Associated with Insulin Sensitivity: a Multi-Center Cohort Study.

J Clin Endocrinol Metab 2021 Apr 11. Epub 2021 Apr 11.

Department of Nutrition, Harvard T.H. Chan School of Public Health, 665 Huntington Avenue, Boston, MA, United States of America.

Context: HDL in humans is composed of a heterogeneous group of particles varying in protein composition as well as biological effects.

Objective: We investigated the prospective associations between HDL subspecies containing and lacking apoC-III at baseline and insulin sensitivity at year 3.

Design, Setting, And Participants: A prospective cohort study of 864 healthy volunteers drawn from the RISC study, a multi-center European clinical investigation, whose recruitment initiated in 2002 with a follow-up of 3 years.

Main Measures: Insulin sensitivity was estimated from an oral glucose tolerance test (OGTT) at baseline and year 3, and by euglycemic-hyperinsulinemic clamp at baseline only. The apolipoprotein concentrations were measured at baseline by a sandwich ELISA-based method.

Results: The two HDL subspecies demonstrated significantly opposite associations with insulin sensitivity at year 3 (p-heterogeneity=0.004). The highest quintile of HDL containing apoC-III was associated with a 1.2% reduction in insulin sensitivity (p-trend=0.02), while the highest quintile of HDL lacking apoC-III was associated with a 1.3% increase (p-trend=0.01), compared to the lowest quintile. No significant association was observed for total HDL, and VLDL and LDL containing apoC-III. ApoC-III contained in HDL was associated with a decrease in insulin sensitivity even more strongly than plasma total apoC-III.

Conclusion: Both HDL containing apoC-III and apoC-III in HDL adversely affect the beneficial properties of HDL on insulin response to glucose. Our results support the potential of HDL-associated apoC-III as a promising target for diabetes prevention and treatment.
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http://dx.doi.org/10.1210/clinem/dgab234DOI Listing
April 2021

Gut microbiota-derived metabolites and risk of coronary artery disease: a prospective study among US men and women.

Am J Clin Nutr 2021 Apr 7. Epub 2021 Apr 7.

Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA, USA.

Background: Accumulating evidence has suggested that human gut microbiota metabolize certain dietary compounds and subsequently produce bioactive metabolites that may exert beneficial or harmful effects on coronary artery disease (CAD) risk.

Objectives: This study examined the joint association of 2 gut microbiota metabolites, enterolactone and trimethylamine N-oxide (TMAO), that originate from intake of plant-based foods and animal products, respectively, in relation to CAD risk.

Methods: A prospective nested case-control study of CAD was conducted among participants who were free of diabetes, cardiovascular disease, and cancer in the Nurses' Health Study II and the Health Professionals Follow-up Study. Plasma concentrations of enterolactone and TMAO, as well as choline and L-carnitine, were assayed among 608 CAD case-control pairs.

Results: A high enterolactone and low TMAO profile was associated with better diet quality, especially higher intake of whole grains and fiber and lower intake of red meats, as well as lower concentrations of plasma triglycerides and C-reactive protein. Participants with a high enterolactone/low TMAO profile had a significantly lower risk of CAD: the multivariate-adjusted OR was 0.58 (95% CI: 0.38, 0.90), compared with participants with a low enterolactone/high TMAO profile. No significant interaction between enterolactone and TMAO on CAD risk was observed. Neither TMAO nor enterolactone alone were associated with CAD risk in pooled analyses. In women, a higher enterolactone concentration was significantly associated with a 54% lower CAD risk (P trend = 0.03), although the interaction by sex was not significant.

Conclusions: Our results show that a profile characterized by high enterolactone and low TMAO concentrations in plasma is linked to a healthful dietary pattern and significantly associated with a lower risk of CAD. Overall, these data suggest that, compared with individual markers, multiple microbiota-derived metabolites may facilitate better differentiation of CAD risk and characterization of the relations between diet, microbiota, and CAD risk.
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http://dx.doi.org/10.1093/ajcn/nqab053DOI Listing
April 2021

A framework for microbiome science in public health.

Nat Med 2021 05 5;27(5):766-774. Epub 2021 Apr 5.

Harvard Chan Microbiome in Public Health Center, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Human microbiome science has advanced rapidly and reached a scale at which basic biology, clinical translation and population health are increasingly integrated. It is thus now possible for public health researchers, practitioners and policymakers to take specific action leveraging current and future microbiome-based opportunities and best practices. Here we provide an outline of considerations for research, education, interpretation and scientific communication concerning the human microbiome and public health. This includes guidelines for population-scale microbiome study design; necessary physical platforms and analysis methods; integration into public health areas such as epidemiology, nutrition, chronic disease, and global and environmental health; entrepreneurship and technology transfer; and educational curricula. Particularly in the near future, there are both opportunities for the incorporation of microbiome-based technologies into public health practice, and a growing need for policymaking and regulation around related areas such as prebiotic and probiotic supplements, novel live-cell therapies and fecal microbiota transplants.
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http://dx.doi.org/10.1038/s41591-021-01258-0DOI Listing
May 2021

Dairy consumption, plasma metabolites, and risk of type 2 diabetes.

Am J Clin Nutr 2021 Mar 19. Epub 2021 Mar 19.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: Epidemiologic studies have reported a modest inverse association between dairy consumption and the risk of type 2 diabetes (T2D). Whether plasma metabolite profiles associated with dairy consumption reflect this relationship remains unknown.

Objectives: We aimed to identify the plasma metabolites associated with total and specific dairy consumption, and to evaluate the association between the identified multi-metabolite profiles and T2D.

Methods: The discovery population included 1833 participants from the Prevención con Dieta Mediterránea (PREDIMED) trial. The confirmatory cohorts included 1522 PREDIMED participants at year 1 of the trial and 4932 participants from the Nurses' Health Studies (NHS), Nurses' Health Study II (NHSII), and Health Professionals Follow-Up Study US-based cohorts. Dairy consumption was assessed using validated FFQs. Plasma metabolites (n = 385) were profiled using LC-MS. We identified the dairy-related metabolite profiles using elastic net regularized regressions with a 10-fold cross-validation procedure. We evaluated the associations between the metabolite profiles and incident T2D in the discovery and the confirmatory cohorts.

Results: Total dairy intake was associated with 38 metabolites. C14:0 sphingomyelin (positive coefficient), C34:0 phosphatidylethanolamine (positive coefficient), and γ-butyrobetaine (negative coefficient) were associated in a directionally similar fashion with total and specific (milk, yogurt, cheese) dairy consumption. The Pearson correlation coefficients between self-reported total dairy intake and predicted total dairy intake based on the corresponding multi-metabolite profile were 0.37 (95% CI, 0.33-0.40) in the discovery cohort and 0.16 (95% CI, 0.13-0.19) in the US confirmatory cohort. After adjusting for T2D risk factors, a higher total dairy intake-related metabolite profile score was associated with a lower T2D risk [HR per 1 SD; discovery cohort: 0.76 (95% CI, 0.63-0.90); US confirmatory cohort: 0.88 (95% CI, 0.78-0.99)].

Conclusions: Total dairy intake was associated with 38 metabolites, including 3 consistently associated with dairy subtypes (C14:0 sphingomyelin, C34:0 phosphatidylethanolamine, γ-butyrobetaine). A score based on the 38 identified metabolites showed an inverse association with T2D risk in Spanish and US populations.
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http://dx.doi.org/10.1093/ajcn/nqab047DOI Listing
March 2021

Quality of Plant-Based Diet and Risk of Total, Ischemic, and Hemorrhagic Stroke.

Neurology 2021 04 10;96(15):e1940-e1953. Epub 2021 Mar 10.

From the Department of Nutrition (M.Y.B., Z.S., F.W., Y.L., E.B.R., W.C.W., F.B.H.), Department of Epidemiology (J.E.M., E.B.R., W.C.W., F.B.H.), Harvard T.H. Chan School of Public Health, Boston, MA; Department of Metabolic Medicine (M.Y.B.), Osaka University Graduate School of Medicine, Japan; Channing Division of Network Medicine (J.E.M., W.C.W., F.B.H.), Department of Medicine, Division of Preventive Medicine (J.E.M.), Department of Medicine, and Division of Women's Health (K.M.R.), Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA, USA.

Objective: To determine whether a healthful plant-based diet is related to lower stroke risk, we examined the associations of plant-based diet quality with risk of total, ischemic, and hemorrhagic stroke.

Methods: The participants were 73,890 women in Nurses' Health Study (NHS; 1984-2016), 92,352 women in NHSII (1991-2017), and 43,266 men in Health Professionals Follow-Up Study (1986-2012) without cardiovascular disease and cancer at baseline. Plant-based diet quality was evaluated by the overall plant-based diet index (PDI), the healthful PDI (hPDI), and the unhealthful PDI (uPDI). Participants who reported that their meat and/or fish intakes were 0 or <1 serving per month were categorized as vegetarians, and others were classified as nonvegetarians. Strokes with available medical records were subtyped as ischemic or hemorrhagic.

Results: During the follow-up, 6,241 total stroke cases (including 3,015 ischemic and 853 hemorrhagic strokes) were documented. Compared to participants with the lowest PDIs, among participants with the highest PDIs, the hazard ratios (HRs) for total stroke were 0.94 (95% confidence interval 0.86-1.03) for PDI, 0.90 (0.83-0.98) for hPDI, and 1.05 (0.96-1.15) for uPDI. Participants in the highest hPDI showed marginally lower HR for ischemic stroke (0.92 [0.82-1.04]) and no consistent associations for hemorrhagic stroke. We observed no association between a vegetarian diet and total stroke (1.00 [0.76-1.32]), although the number of cases was small.

Conclusion: Lower risk of total stroke was observed by those who adhered to a healthful plant-based diet.
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http://dx.doi.org/10.1212/WNL.0000000000011713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166423PMC
April 2021

Reply: Food as Medicine: Prevention Is Better, but Could It Cure?

Authors:
Jun Li Frank B Hu

J Am Coll Cardiol 2021 Mar;77(9):1267-1268

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http://dx.doi.org/10.1016/j.jacc.2020.12.049DOI Listing
March 2021

Fruit and Vegetable Intake and Mortality: Results From 2 Prospective Cohort Studies of US Men and Women and a Meta-Analysis of 26 Cohort Studies.

Circulation 2021 Apr 1;143(17):1642-1654. Epub 2021 Mar 1.

Channing Division for Network Medicine (D.D.W., S.N.B., B.A.R., Q.S., E.L.G., E.B.R., J.E.M., W.C.W., M.J.S., F.B.H.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA.

Background: The optimal intake levels of fruit and vegetables for maintaining long-term health are uncertain.

Methods: We followed 66 719 women from the Nurses' Health Study (1984-2014) and 42 016 men from the Health Professionals Follow-up Study (1986-2014) who were free from cardiovascular disease (CVD), cancer, and diabetes at baseline. Diet was assessed using a validated semiquantitative food frequency questionnaire at baseline and updated every 2 to 4 years. We also conducted a dose-response meta-analysis, including results from our 2 cohorts and 24 other prospective cohort studies.

Results: We documented 33 898 deaths during the follow-up. After adjustment for known and suspected confounding variables and risk factors, we observed nonlinear inverse associations of fruit and vegetable intake with total mortality and cause-specific mortality attributable to cancer, CVD, and respiratory disease (all <0.001). Intake of ≈5 servings per day of fruit and vegetables, or 2 servings of fruit and 3 servings of vegetables, was associated with the lowest mortality, and above that level, higher intake was not associated with additional risk reduction. In comparison with the reference level (2 servings/d), daily intake of 5 servings of fruit and vegetables was associated with hazard ratios (95% CI) of 0.87 (0.85-0.90) for total mortality, 0.88 (0.83-0.94) for CVD mortality, 0.90 (0.86-0.95) for cancer mortality, and 0.65 (0.59-0.72) for respiratory disease mortality. The dose-response meta-analysis that included 145 015 deaths accrued in 1 892 885 participants yielded similar results (summary risk ratio of mortality for 5 servings/d=0.87 [95% CI, 0.85-0.88]; <0.001). Higher intakes of most subgroups of fruits and vegetables were associated with lower mortality, with the exception of starchy vegetables such as peas and corn. Intakes of fruit juices and potatoes were not associated with total and cause-specific mortality.

Conclusions: Higher intakes of fruit and vegetables were associated with lower mortality; the risk reduction plateaued at ≈5 servings of fruit and vegetables per day. These findings support current dietary recommendations to increase intake of fruits and vegetables, but not fruit juices and potatoes.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084888PMC
April 2021

The gut microbiome modulates the protective association between a Mediterranean diet and cardiometabolic disease risk.

Nat Med 2021 02 11;27(2):333-343. Epub 2021 Feb 11.

Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

To address how the microbiome might modify the interaction between diet and cardiometabolic health, we analyzed longitudinal microbiome data from 307 male participants in the Health Professionals Follow-Up Study, together with long-term dietary information and measurements of biomarkers of glucose homeostasis, lipid metabolism and inflammation from blood samples. Here, we demonstrate that a healthy Mediterranean-style dietary pattern is associated with specific functional and taxonomic components of the gut microbiome, and that its protective associations with cardiometabolic health vary depending on microbial composition. In particular, the protective association between adherence to the Mediterranean diet and cardiometabolic disease risk was significantly stronger among participants with decreased abundance of Prevotella copri. Our findings advance the concept of precision nutrition and have the potential to inform more effective and precise dietary approaches for the prevention of cardiometabolic disease mediated through alterations in the gut microbiome.
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http://dx.doi.org/10.1038/s41591-020-01223-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8186452PMC
February 2021

Preexisting Type 2 Diabetes and Survival among Patients with Colorectal Cancer.

Cancer Epidemiol Biomarkers Prev 2021 Apr 2;30(4):757-764. Epub 2021 Feb 2.

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.

Background: Type 2 diabetes increases risk of developing colorectal cancer, but the association of preexisting diabetes with colorectal cancer survival remains unclear.

Methods: We analyzed survival by diabetes status at cancer diagnosis among 4,038 patients with colorectal cancer from two prospective U.S. cohorts. Cox proportional hazards regression was used to calculate HRs and 95% confidence intervals (CI) for overall and cause-specific mortality, with adjustment for tumor characteristics and lifestyle factors.

Results: In the first 5 years after colorectal cancer diagnosis, diabetes was associated with a modest increase in overall mortality in women (HR, 1.22; 95% CI, 1.00-1.49), but not in men (HR, 0.83; 95% CI, 0.62-1.12; heterogeneity by sex = 0.04). Beyond 5 years, diabetes was associated with substantially increased overall mortality with no evidence of sex heterogeneity; in women and men combined, the HRs were 1.45 (95% CI, 1.09-1.93) during >5-10 years and 2.58 (95% CI, 1.91-3.50) during >10 years. Compared with those without diabetes, patients with colorectal cancer and diabetes had increased mortality from other malignancies (HR, 1.78; 95% CI, 1.18-2.67) and cardiovascular disease (HR, 1.93; 95% CI, 1.29-2.91). Only women with diabetes for more than 10 years had increased mortality from colorectal cancer (HR, 1.33; 95% CI, 1.01-1.76).

Conclusions: Among patients with colorectal cancer, preexisting diabetes was associated with increased risk of long-term mortality, particularly from other malignancies and cardiovascular disease.

Impact: Our findings highlight the importance of cardioprotection and cancer prevention to colorectal cancer survivors with diabetes.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026573PMC
April 2021

Changes in Plant-Based Diet Indices and Subsequent Risk of Type 2 Diabetes in Women and Men: Three U.S. Prospective Cohorts.

Diabetes Care 2021 Mar 13;44(3):663-671. Epub 2021 Jan 13.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA

Objective: We evaluated the associations between changes in plant-based diets and subsequent risk of type 2 diabetes.

Research Design And Methods: We prospectively followed 76,530 women in the Nurses' Health Study (NHS) (1986-2012), 81,569 women in NHS II (1991-2017), and 34,468 men in the Health Professionals Follow-up Study (1986-2016). Adherence to plant-based diets was assessed every 4 years with the overall plant-based diet index (PDI), healthful PDI (hPDI), and unhealthful PDI (uPDI). We used multivariable Cox proportional hazards models to estimate hazard ratios (HRs). We pooled results of the three cohorts using meta-analysis.

Results: We documented 12,627 cases of type 2 diabetes during 2,955,350 person-years of follow-up. After adjustment for initial BMI and initial and 4-year changes in alcohol intake, smoking, physical activity, and other factors, compared with participants whose indices remained relatively stable (±3%), participants with the largest decrease (>10%) in PDI and hPDI over 4 years had a 12-23% higher diabetes risk in the subsequent 4 years (pooled HR, PDI 1.12 [95% CI 1.05, 1.20], hPDI 1.23 [1.16, 1.31]). Each 10% increment in PDI and hPDI over 4 years was associated with a 7-9% lower risk (PDI 0.93 [0.91, 0.95], hPDI 0.91 [0.87, 0.95]). Changes in uPDI were not associated with diabetes risk. Weight changes accounted for 6.0-35.6% of the associations between changes in PDI and hPDI and diabetes risk.

Conclusions: Improving adherence to overall and healthful plant-based diets was associated with a lower risk of type 2 diabetes, whereas decreased adherence to such diets was associated with a higher risk.
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http://dx.doi.org/10.2337/dc20-1636DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7896264PMC
March 2021

Prioritized Research for the Prevention, Treatment, and Reversal of Chronic Disease: Recommendations From the Lifestyle Medicine Research Summit.

Front Med (Lausanne) 2020 22;7:585744. Epub 2020 Dec 22.

University of Pittsburgh Medical Center Health Plan/WorkPartners, Pittsburgh, PA, United States.

Declining life expectancy and increasing all-cause mortality in the United States have been associated with unhealthy behaviors, socioecological factors, and preventable disease. A growing body of basic science, clinical research, and population health evidence points to the benefits of healthy behaviors, environments and policies to maintain health and prevent, treat, and reverse the root causes of common chronic diseases. Similarly, innovations in research methodologies, standards of evidence, emergence of unique study cohorts, and breakthroughs in data analytics and modeling create new possibilities for producing biomedical knowledge and clinical translation. To understand these advances and inform future directions research, The Lifestyle Medicine Research Summit was convened at the University of Pittsburgh on December 4-5, 2019. The Summit's goal was to review current status and define research priorities in the six core areas of lifestyle medicine: plant-predominant nutrition, physical activity, sleep, stress, addictive behaviors, and positive psychology/social connection. Forty invited subject matter experts (1) reviewed existing knowledge and gaps relating lifestyle behaviors to common chronic diseases, such as cardiovascular disease, diabetes, many cancers, inflammatory- and immune-related disorders and other conditions; and (2) discussed the potential for applying cutting-edge molecular, cellular, epigenetic and emerging science knowledge and computational methodologies, research designs, and study cohorts to accelerate clinical applications across all six domains of lifestyle medicine. Notably, federal health agencies, such as the Department of Defense and Veterans Administration have begun to adopt "whole-person health and performance" models that address these lifestyle and environmental root causes of chronic disease and associated morbidity, mortality, and cost. Recommendations strongly support leveraging emerging research methodologies, systems biology, and computational modeling in order to accelerate effective clinical and population solutions to improve health and reduce societal costs. New and alternative hierarchies of evidence are also be needed in order to assess the quality of evidence and develop evidence-based guidelines on lifestyle medicine. Children and underserved populations were identified as prioritized groups to study. The COVID-19 pandemic, which disproportionately impacts people with chronic diseases that are amenable to effective lifestyle medicine interventions, makes the Summit's findings and recommendations for future research particularly timely and relevant.
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http://dx.doi.org/10.3389/fmed.2020.585744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783318PMC
December 2020

THE RELATIONSHIP BETWEEN INFLAMMATORY DIETARY PATTERN AND INCIDENCE OF PERIODONTITIS.

Br J Nutr 2021 Jan 8:1-36. Epub 2021 Jan 8.

Department of Epidemiology, Harvard T.H. Chan School of Public Health 677 Huntington Ave, Boston, MA02115, USA.

The long-term inflammatory impact of diet could potentially elevate the risk of periodontal disease through modification of systemic inflammation. The aim of the present study was to prospectively investigate the associations between a food based, reduced rank regression (RRR) derived, empirical dietary inflammatory pattern (EDIP) and incidence of periodontitis. The study population was composed of 34,940 men from the Health Professionals Follow-Up Study, who were free of periodontal disease and major illnesses at baseline (1986). Participants provided medical and dental history through mailed questionnaires every 2 years, and dietary data through validated semi-quantitative food frequency questionnaires every 4 years. We used Cox proportional hazard models to examine the associations between EDIP scores and validated self-reported incidence of periodontal disease over a 24-year follow-up period. No overall association between EDIP and the risk of periodontitis was observed; the hazard ratio comparing the highest EDIP quintile (most proinflammatory diet) to the lowest quintile was 0.99 (95% confidence interval: 0.89 -1.10, p-value for trend = 0.97). A secondary analysis showed that among obese non-smokers (i.e. never and former smokers at baseline), the hazard ratio for periodontitis comparing the highest EDIP quintile to the lowest was 1.39 (95% confidence interval: 0.98 -1.96, p-value for trend = 0.03). In conclusion, no overall association was detected between EDIP and incidence of self-reported periodontitis in the study population. From the subgroups evaluated EDIP was significantly associated with increased risk of periodontitis only among nonsmokers who were obese. Hence, this association must be interpreted with caution.
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http://dx.doi.org/10.1017/S0007114520005231DOI Listing
January 2021

Walnut Consumption, Plasma Metabolomics, and Risk of Type 2 Diabetes and Cardiovascular Disease.

J Nutr 2021 02;151(2):303-311

Universitat Rovira i Virgili, Departament de Bioquímica i Biotecnologia, Unitat de Nutrició Humana, Hospital Universitari San Joan de Reus, Reus, Spain.

Background: Walnut consumption is associated with lower risk of type 2 diabetes (T2D) and cardiovascular disease (CVD). However, it is unknown whether plasma metabolites related to walnut consumption are also associated with lower risk of cardiometabolic diseases.

Objectives: The study aimed to identify plasma metabolites associated with walnut consumption and evaluate the prospective associations between the identified profile and risk of T2D and CVD.

Methods: The discovery population included 1833 participants at high cardiovascular risk from the PREvención con DIeta MEDiterránea (PREDIMED) study with available metabolomics data at baseline. The study population included 57% women (baseline mean BMI (in kg/m2): 29.9; mean age: 67 y). A total of 1522 participants also had available metabolomics data at year 1 and were used as the internal validation population. Plasma metabolomics analyses were performed using LC-MS. Cross-sectional associations between 385 known metabolites and walnut consumption were assessed using elastic net continuous regression analysis. A 10-cross-validation (CV) procedure was used, and Pearson correlation coefficients were assessed between metabolite weighted models and self-reported walnut consumption in each pair of training-validation data sets within the discovery population. We further estimated the prospective associations between the identified metabolite profile and incident T2D and CVD using multivariable Cox regression models.

Results: A total of 19 metabolites were significantly associated with walnut consumption, including lipids, purines, acylcarnitines, and amino acids. Ten-CV Pearson correlation coefficients between self-reported walnut consumption and the plasma metabolite profile were 0.16 (95% CI: 0.11, 0.20) in the discovery population and 0.15 (95% CI: 0.10, 0.20) in the validation population. The metabolite profile was inversely associated with T2D incidence (HR per 1 SD: 0.83; 95% CI: 0.71, 0.97; P = 0.02). For CVD incidence, the HR per 1-SD was 0.71 (95% CI: 0.60, 0.85; P < 0.001).

Conclusions: A metabolite profile including 19 metabolites was associated with walnut consumption and with a lower risk of incident T2D and CVD in a Mediterranean population at high cardiovascular risk.
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http://dx.doi.org/10.1093/jn/nxaa374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850062PMC
February 2021

Genetic Predisposition to Coronary Artery Disease in Type 2 Diabetes Mellitus.

Circ Genom Precis Med 2020 12 13;13(6):e002769. Epub 2020 Aug 13.

The Usher Institute of Population Health Sciences & Informatics (A.D.M.), University of Edinburgh, Edinburgh, U.K.

Background: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D).

Methods: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D).

Results: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background.

Conclusions: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.
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http://dx.doi.org/10.1161/CIRCGEN.119.002769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748049PMC
December 2020

Plasma Metabolomic Profiles of Glycemic Index, Glycemic Load, and Carbohydrate Quality Index in the PREDIMED Study.

J Nutr 2021 01;151(1):50-58

Universitat Rovira i Virgili, Biochemistry and Biotechnology Department, Human Nutrition Unit, Reus, Spain.

Background: The quality of carbohydrate consumed, assessed by the glycemic index (GI), glycemic load (GL), or carbohydrate quality index (CQI), affects the postprandial glycemic and insulinemic responses, which have been implicated in the etiology of several chronic diseases. However, it is unclear whether plasma metabolites involved in different biological pathways could provide functional insights into the role of carbohydrate quality indices in health.

Objectives: We aimed to identify plasma metabolomic profiles associated with dietary GI, GL, and CQI.

Methods: The present study is a cross-sectional analysis of 1833 participants with overweight/obesity (mean age = 67 y) from 2 case-cohort studies nested within the PREDIMED (Prevención con Dieta Mediterránea) trial. Data extracted from validated FFQs were used to estimate the GI, GL, and CQI. Plasma concentrations of 385 metabolites were profiled with LC coupled to MS and associations of these metabolites with those indices were assessed with elastic net regression analyses.

Results: A total of 58, 18, and 57 metabolites were selected for GI, GL, and CQI, respectively. Choline, cotinine, γ-butyrobetaine, and 36:3 phosphatidylserine plasmalogen were positively associated with GI and GL, whereas they were negatively associated with CQI. Fructose-glucose-galactose was negatively and positively associated with GI/GL and CQI, respectively. Consistent associations of 21 metabolites with both GI and CQI were found but in opposite directions. Negative associations of kynurenic acid, 22:1 sphingomyelin, and 38:6 phosphatidylethanolamine, as well as positive associations of 32:1 phosphatidylcholine with GI and GL were also observed. Pearson correlation coefficients between GI, GL, and CQI and the metabolomic profiles were 0.30, 0.22, and 0.27, respectively.

Conclusions: The GI, GL, and CQI were associated with specific metabolomic profiles in a Mediterranean population at high cardiovascular disease risk. Our findings may help in understanding the role of dietary carbohydrate indices in the development of cardiometabolic disorders. This trial was registered at isrctn.com as ISRCTN35739639.
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http://dx.doi.org/10.1093/jn/nxaa345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779218PMC
January 2021

Sweetened beverages and risk of frailty among older women in the Nurses' Health Study: A cohort study.

PLoS Med 2020 12 8;17(12):e1003453. Epub 2020 Dec 8.

Department of Preventive Medicine and Public Health, School of Medicine, Universidad Autónoma de Madrid-IdiPaz, Madrid, Spain.

Background: Consumption of sugar-sweetened beverages (SSBs) has been consistently associated with a higher risk of obesity, type 2 diabetes, cardiovascular disease, and premature mortality, whereas evidence for artificially sweetened beverages (ASBs) and fruit juices on health is less solid. The aim of this study was to evaluate the consumption of SSBs, ASBs, and fruit juices in association with frailty risk among older women.

Methods And Findings: We analyzed data from 71,935 women aged ≥60 (average baseline age was 63) participating in the Nurses' Health Study (NHS), an ongoing cohort study initiated in 1976 among female registered nurses in the United States. Consumption of beverages was derived from 6 repeated food frequency questionnaires (FFQs) administered between 1990 and 2010. Frailty was defined as having at least 3 of the following 5 criteria from the FRAIL scale: fatigue, poor strength, reduced aerobic capacity, having ≥5 chronic illnesses, and weight loss ≥5%. The occurrence of frailty was assessed every 4 years from 1992 to 2014. During 22 years of follow-up, we identified 11,559 incident cases of frailty. Consumption of SSBs was associated with higher risk of frailty after adjustment for diet quality, body mass index (BMI), smoking status, and medication use, specifically, the relative risks (RRs) and 95% confidence interval (95% CI) for ≥2 serving/day versus no SSB consumption was 1.32 (1.10, 1.57); p-value <0.001. ASBs were also associated with frailty [RR ≥2 serving/day versus no consumption: 1.28 (1.17, 1.39); p-value <0.001]. Orange juice was associated with lower risk of frailty [RR ≥1 serving/day versus no consumption: 0.82 (0.76, 0.87); p-value <0.001], whereas other juices were associated with a slightly higher risk [RR ≥1 serving/day versus no consumption: 1.15 (1.03, 1.28); p-value <0.001]. A limitation of this study is that, due to self-reporting of diet and frailty, certain misclassification bias cannot be ruled out; also, some residual confounding may persist.

Conclusions: In this study, we observed that consumption of SSBs and ASBs was associated with a higher risk of frailty. However, orange juice intake showed an inverse association with frailty. These results need to be confirmed in further studies using other frailty definitions.
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http://dx.doi.org/10.1371/journal.pmed.1003453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7723265PMC
December 2020

Lipid Profiles and Heart Failure Risk: Results From Two Prospective Studies.

Circ Res 2021 Feb 4;128(3):309-320. Epub 2020 Dec 4.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (C.W., M.G.-F., J.L., C.-H.L., M.A.M.-G., F.B.H.).

Rationale: Altered lipid metabolism has been implicated in heart failure (HF) development, but no prospective studies have examined comprehensive lipidomics data and subsequent risk of HF.

Objective: We aimed to link single lipid metabolites and lipidomics networks to the risk of developing HF.

Methods And Results: Discovery analyses were based on 216 targeted lipids in a case-control study (331 incident HF cases and 507 controls, matched by age, sex, and study center), nested within the PREDIMED (Prevención con Dieta Mediterránea) study. Associations of single lipids were examined in conditional logistic regression models. Furthermore, lipidomics networks were linked to HF risk in a multistep workflow, including machine learning-based identification of the HF-related network clusters, and regression-based discovery of the HF-related lipid patterns within these clusters. If available, significant findings were externally validated in a subsample of the EPIC-Potsdam cohort (2414 at-risk participants, including 87 incident HF cases). After confounder-adjustments, 2 lipids were significantly associated with HF risk in both cohorts: CER (ceramide) 16:0 (relative risk [RR] per SD in PREDIMED, 1.28 [95% CI, 1.13-1.47]) and phosphatidylcholine 32_0 (RR per SD in PREDIMED, 1.23 [95% CI, 1.08-1.41]). Additionally, lipid patterns in several network clusters were associated with HF risk in PREDIMED. Adjusted for standard risk factors, an internally cross-validated score based on the significant HF-related lipids that were identified in the network analysis in PREDIMED was associated with a higher HF risk (20 lipids, RR per SD, 2.33 [95% CI, 1.93%-2.81%). Moreover, a lipid score restricted to the externally available lipids was significantly associated with HF incidence in both cohorts (6 lipids, RRs per SD, 1.30 [95% CI, 1.14-1.47] in PREDIMED, and 1.46 [95% CI, 1.17-1.82] in EPIC-Potsdam).

Conclusions: Our study identified and validated 2 lipid metabolites and several lipidomics patterns as potential novel biomarkers of HF risk. Lipid profiling may capture preclinical molecular alterations that predispose for incident HF. Registration: URL: https://www.isrctn.com/ISRCTN35739639; Unique identifier: ISRCTN35739639.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.317883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864881PMC
February 2021

Red meat intake and risk of coronary heart disease among US men: prospective cohort study.

BMJ 2020 12 2;371:m4141. Epub 2020 Dec 2.

Department of Nutrition, Harvard TH Chan School of Public Health, 655 Huntington Avenue, Boston, MA 02115, USA

Objectives: To study total, processed, and unprocessed red meat in relation to risk of coronary heart disease (CHD) and to estimate the effects of substituting other protein sources for red meat with CHD risk.

Design: Prospective cohort study with repeated measures of diet and lifestyle factors.

Setting: Health Professionals Follow-Up Study cohort, United States, 1986-2016.

Participants: 43 272 men without cardiovascular disease or cancer at baseline.

Main Outcome Measures: The primary outcome was total CHD, comprised of acute non-fatal myocardial infarction or fatal CHD. Cox models were used to estimate hazard ratios and 95% confidence intervals across categories of red meat consumption. Substitution analyses were conducted by comparing coefficients for red meat and the alternative food in models, including red meat and alternative foods as continuous variables.

Results: During 1 023 872 person years of follow-up, 4456 incident CHD events were documented of which 1860 were fatal. After multivariate adjustment for dietary and non-dietary risk factors, total, unprocessed, and processed red meat intake were each associated with a modestly higher risk of CHD (hazard ratio for one serving per day increment: 1.12 (95% confidence interval 1.06 to 1.18) for total red meat, 1.11 (1.02 to 1.21) for unprocessed red meat, and 1.15 (1.06 to 1.25) for processed red meat). Compared with red meat, the intake of one serving per day of combined plant protein sources (nuts, legumes, and soy) was associated with a lower risk of CHD (0.86 (0.80 to 0.93) compared with total red meat, 0.87 (0.79 to 0.95) compared with unprocessed red meat, and 0.83 (0.76 to 0.91) compared with processed red meat). Substitutions of whole grains and dairy products for total red meat and eggs for processed red meat were also associated with lower CHD risk.

Conclusions: Substituting high quality plant foods such as legumes, nuts, or soy for red meat might reduce the risk of CHD. Substituting whole grains and dairy products for total red meat, and eggs for processed red meat, might also reduce this risk.
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http://dx.doi.org/10.1136/bmj.m4141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8030119PMC
December 2020

Choline Metabolism and Risk of Atrial Fibrillation and Heart Failure in the PREDIMED Study.

Clin Chem 2021 Jan;67(1):288-297

Universitat Rovira i Virgili, Departament de Bioquímica i Biotecnologia, Unitat de Nutrició, Reus, Spain.

Background: Few studies have examined the associations of trimethylamine-N-oxide (TMAO) and its precursors (choline, betaine, dimethylglycine, and L-carnitine) with the risk of atrial fibrillation (AF) and heart failure (HF). This study sought to investigate these associations.

Methods: Prospective associations of these metabolites with incident AF and HF were examined among participants at high cardiovascular risk in the PREDIMED study (PREvención con DIeta MEDiterránea) after follow-up for about 10 years. Two nested case-control studies were conducted, including 509 AF incident cases matched to 618 controls and 326 HF incident cases matched to 426 controls. Plasma levels of TMAO and its precursors were semi-quantitatively profiled with liquid chromatography tandem mass spectrometry. Odds ratios were estimated with multivariable conditional logistic regression models.

Results: After adjustment for classical risk factors and accounting for multiple testing, participants in the highest quartile vs. the lowest quartile of baseline choline and betaine levels had a higher risk of AF [OR (95% CI): 1.85 (1.30-2.63) and 1.57 (1.09-2.24), respectively]. The corresponding OR for AF for extreme quartiles of dimethylglycine was 1.39 (0.99-1.96). One SD increase in log-transformed dimethylglycine was positively associated with AF risk (OR, 1.17; 1.03-1.33). The corresponding ORs for HF for extreme quartiles of choline, betaine, and dimethylglycine were 2.51 (1.57-4.03), 1.65 (1.00-2.71) and 1.65 (1.04-2.61), respectively. TMAO and L-carnitine levels were not associated with AF or HF.

Conclusions: Our findings support the role of the choline metabolic pathway in the pathogenesis of AF and HF.
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http://dx.doi.org/10.1093/clinchem/hvaa224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7793226PMC
January 2021

Incident Type 2 Diabetes Duration and Cancer Risk: A Prospective Study in Two US Cohorts.

J Natl Cancer Inst 2021 Apr;113(4):381-389

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA.

Background: The influence of type 2 diabetes mellitus (T2D) duration on cancer incidence remains poorly understood.

Methods: We prospectively followed for cancer incidence 113 429 women in the Nurses' Health Study (1978-2014) and 45 604 men in the Health Professionals Follow-up Study (1988-2014) who were free of diabetes and cancer at baseline. Cancer incidences were ascertained by review of medical records.

Results: In the multivariable-adjusted model incident, T2D was associated with higher risk of cancers in the colorectum, lung, pancreas, esophagus, liver, thyroid, breast, and endometrium. The pooled hazard ratios (HRs) ranged from 1.21 (95% confidence interval [CI] = 1.06 to 1.38) for colorectal cancer to 3.39 (95% CI = 2.24 to 5.12) for liver cancer. For both composite cancer outcomes and individual cancers, the elevated risks did not further increase after 8 years of T2D duration. The hazard ratio for total cancer was 1.28 (95% CI = 1.17 to 1.40) for T2D duration of 4.1-6.0 years, 1.37 (95% CI = 1.25 to 1.50) for 6.1-8.0 years, 1.21 (95% CI = 1.09 to 1.35) for 8.1-10.0 years, and 1.04 (95% CI = 0.95 to 1.14) after 15.0 years. In a cross-sectional analysis, a higher level of plasma C-peptide was found among participants with prevalent T2D of up to 8 years than those without T2D, whereas a higher level of HbA1c was found for those with prevalent T2D of up to 15 years.

Conclusions: Incident T2D was associated with higher cancer risk, which peaked at approximately 8 years after diabetes diagnosis. Similar duration-dependent pattern was observed for plasma C-peptide. Our findings support a role of hyperinsulinemia in cancer development.
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http://dx.doi.org/10.1093/jnci/djaa141DOI Listing
April 2021